Dipartimento di Scienze e Innovazione Tecnologica , Università del Piemonte Orientale , Viale Michel 11 , 15121 Alessandria , Italy.
J Med Chem. 2019 Apr 11;62(7):3395-3406. doi: 10.1021/acs.jmedchem.8b01860. Epub 2019 Mar 27.
The synthesis, characterization, and in vitro activity of a cyclohexane-1 R,2 R-diamine-based Pt(IV) derivative containing the histone deacetylase inhibitor rac-2-(2-propynyl)octanoato, namely, ( OC-6-44)-acetatodichlorido(cyclohexane-1 R,2 R-diamine)( rac-2-(2-propynyl)octanoato)platinum(IV), are reported together with those of its isomers containing enantiomerically enriched axial ligands. These Pt(IV) complexes showed comparable activity, of 2 orders of magnitude higher than reference drug oxaliplatin on three human (HCT 116, SW480, and HT-29) and one mouse (CT26) colon cancer cell lines. In vivo experiments were carried out on immunocompetent BALB/c mice bearing the same syngeneic tumor. The complex ( OC-6-44)-acetatodichlorido(cyclohexane-1 R,2 R-diamine)( rac-2-(2-propynyl)octanoato)platinum(IV) showed higher tumor mass Pt accumulation than oxaliplatin, due to its higher lipophilicity, with negligible nephro- and hepatotoxicities when administered intravenously. A remarkable tumor mass invasion by cytotoxic CD8 T lymphocytes, following the Pt(IV) treatment, indicated a strong induction of immunogenic cell death.
报道了一种基于环己烷-1R,2R-二胺的 Pt(IV) 衍生物的合成、表征和体外活性，该衍生物含有组蛋白去乙酰化酶抑制剂 rac-2-(2-丙炔基)辛酸酯，即（OC-6-44）-醋酸二氯ido（环己烷-1R,2R-二胺）（rac-2-(2-丙炔基)辛酸酯）铂（IV），以及其含有对映体富集轴向配体的异构体。这些 Pt(IV) 配合物表现出相当的活性，在三种人（HCT 116、SW480 和 HT-29）和一种鼠（CT26）结肠癌细胞系上的活性比参考药物奥沙利铂高 2 个数量级。在携带相同同源肿瘤的免疫功能正常的 BALB/c 小鼠中进行了体内实验。由于其较高的亲脂性，配合物（OC-6-44）-醋酸二氯ido（环己烷-1R,2R-二胺）（rac-2-(2-丙炔基)辛酸酯）铂（IV）比奥沙利铂具有更高的肿瘤质量 Pt 积累，静脉给药时几乎没有肾毒性和肝毒性。在 Pt(IV) 治疗后，细胞毒性 CD8 T 淋巴细胞显著浸润肿瘤，表明强烈诱导了免疫原性细胞死亡。
